title: Phenotypic polarization of activated astrocytes: the critical role of lipocalin-2 in the classical inflammatory activation of astrocytes.
abstract: Astrocytes provide structural and functional support for neurons, as well as display neurotoxic or neuroprotective phenotypes depending upon the presence of an immune or inflammatory microenvironment. This study was undertaken to characterize multiple phenotypes of activated astrocytes and to investigate the regulatory mechanisms involved. We report that activated astrocytes in culture exhibit two functional phenotypes with respect to pro- or anti-inflammatory gene expression, glial fibrillary acidic protein expression, and neurotoxic or neuroprotective activities. The two distinct functional phenotypes of astrocytes were also demonstrated in a mouse neuroinflammation model, which showed pro- or anti-inflammatory gene expression in astrocytes following challenge with classical or alternative activation stimuli; similar results were obtained in the absence of microglia. Subsequent studies involving recombinant lipocalin-2 (LCN2) protein treatment or Lcn2-deficient mice indicated that the pro- or anti-inflammatory functionally polarized phenotypes of astrocytes and their intracellular signaling pathway were critically regulated by LCN2 under in vitro and in vivo conditions. Astrocyte-derived LCN2 promoted classical proinflammatory activation of astrocytes but inhibited IL-4-STAT6 signaling, a canonical pathway involved in alternative anti-inflammatory activation. Our results suggest that the secreted protein LCN2 is an autocrine modulator of the functional polarization of astrocytes in the presence of immune or inflammatory stimuli and that LCN2 could be targeted therapeutically to dampen proinflammatory astrocytic activation and related pathologies in the CNS.
authors.affiliation: Department of Pharmacology, Brain Science and Engineering Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Korea;
authors.forename: Eunha
authors.initials: E
authors.lastname: Jang
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Shinrye
authors.initials: S
authors.lastname: Lee
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Jung-Wan
authors.initials: JW
authors.lastname: Seo
authors.forename: Myungwon
authors.initials: M
authors.lastname: Jin
authors.forename: Maan-Gee
authors.initials: MG
authors.lastname: Lee
authors.forename: Il-Sung
authors.initials: IS
authors.lastname: Jang
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000276:immunology*; D016764:Cell Polarity; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C071332:Lcn2 protein, mouse; D015847:Interleukin-4